Abstract
Foxn1Delta/Delta mutants have a block in thymic epithelial cell differentiation at an intermediate progenitor stage, resulting in reduced thymocyte cellularity and blocks at the double-negative and double-positive stages. Whereas naive single-positive thymocytes were reduced >500-fold in the adult Foxn1Delta/Delta thymus, peripheral T cell numbers were reduced only 10-fold. The current data shows that Foxn1Delta/Delta peripheral T cells had increased expression of activation markers and the ability to produce IL-2 and IFN-gamma. These cells acquired this profile immediately after leaving the thymus as early as the newborn stage and maintained high steady-state proliferation in vivo but decreased proliferation in response to TCR stimulation in vitro. Single-positive thymocytes and naive T cells also had constitutively low alphabetaTCR and IL7R expression. These cells also displayed reduced ability to undergo homeostatic proliferation and increased rates of apoptosis. Although the frequency of Foxp3+CD4+CD25+ T cells was normal in Foxn1Delta/Delta mutant mice, these cells failed to have suppressor function, resulting in reduced regulatory T cell activity. Recent data from our laboratory suggest that T cells in the Foxn1Delta/Delta thymus develop from atypical progenitor cells via a noncanonical pathway. Our results suggest that the phenotype of peripheral T cells in Foxn1Delta/Delta mutant mice is the result of atypical progenitor cells developing in an abnormal thymic microenvironment with a deficient TCR and IL7 signaling system.
Highlights
Our results suggest that the phenotype of peripheral T cells in Foxn1⌬/⌬ mutant mice is the result of atypical progenitor cells developing in an abnormal thymic microenvironment with a deficient TCR and IL7 signaling system
In addition to the drop in total T cell number, the mean fluorescence intensity of CD4 and CD8 expression on the surface of Foxn1⌬/⌬ T cells was reduced, indicating that the expression of both molecules on the T cell surface was down-regulated. This result was consistent with our previous data showing that surface TCR was reduced on adult SP thymocytes [25]
The percentages of CD44highCD62Llow/Ϫfor both genotypes is essentially zero at newborn stage, tracks behind the appearance of cells in the periphery. These results indicated that the memory-like phenotype is a post-thymus event and that T cells acquire the memory phenotype very soon after they emigrate from the thymus into the periphery
Summary
These results indicate that both CD4ϩ and CD8ϩ T cells from Foxn1⌬/⌬ mice have the ability to produce cytokines even more rapidly than cells from control mice, which is consistent with a memory phenotype. Transferred cells from Foxn1⌬/⌬ mice displayed a low percentage of rapidly proliferating cells in both RagϪ/Ϫ and wild-type hosts (Fig. 5, a and b).
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